| The histone methyltransferase inhibitor DZNep upregulates TXNIP, increases ROS production, and targets leukemia cells in AML. | |
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MedLine Citation:
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PMID: 21734239 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Recent studies have shown that 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, disrupts polycomb-repressive complex 2 (PRC2), and preferentially induces apoptosis in cancer cells, including acute myeloid leukemia (AML). However, the underlying molecular mechanisms are not well understood. The present study demonstrates that DZNep induces robust apoptosis in AML cell lines, primary cells, and targets CD34+CD38- leukemia stem cell (LSC)-enriched subpopulations. Using RNA interference (RNAi), gene expression profiling, and chromatin immunoprecipitation (ChIP), we identified that TXNIP, a major redox control molecule, plays a crucial role in DZNep-induced apoptosis. We show that disruption of PRC2, either by DZNep treatment or EZH2 knockdown, reactivates TXNIP, inhibits thioredoxin activity and increases reactive oxygen species (ROS), leading to apoptosis. Furthermore, we show that TXNIP is downregulated in AML and is a direct target of PRC2-mediated gene silencing. Consistent with the ROS accumulation upon DZNep treatment, we also see a signature of endoplasmic reticulum (ER)-stress regulated genes, commonly associated with cell survival, downregulated by DZNep. Taken together, we uncover a novel molecular mechanism of DZNep-mediated apoptosis and propose that EZH2 may be a potential new target for epigenetic treatment in AML. |
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Authors:
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Jianbiao Zhou; Chonglei Bi; Lip-Lee Cheong; Sylvia Mahara; Shaw-Cheng Liu; Kian-Ghee Tay; Tze-Loong Koh; Qiang Yu; Wee Joo Chng |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-6 |
Journal Detail:
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Title: Blood Volume: - ISSN: 1528-0020 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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